Embodiments of the invention are generally directed to methods for specifying (and optionally fabricating) an object to be fabricated; more particularly, to a method for specifying (and optionally fabricating) an object to be fabricated by 3-D printing of arbitrarily defined functionally graded materials via solid freeform fabrication; and most particularly, to a method for specifying (and optionally fabricating) living tissue and other functionally graded, heterogeneous objects characterized by material heterogeneity (or blending) on a local scale.
Solid freeform fabrication (“SFF”) is the name given to a class of manufacturing methods that allow the fabrication of three-dimensional structures directly from computer-aided design (“CAD”) data. SFF processes are generally additive, in that material is selectively deposited to construct the object to be fabricated rather than removed from a block or billet. Most SFF processes are also layered, meaning that a geometrical description of the object to be fabricated is cut by a set of parallel surfaces (planar or curved), and the intersections of the object and each surface, referred to as slices or layers, are fabricated sequentially. Together, these two properties mean that SFF processes are subject to very different constraints than traditional material removal-based manufacturing. Nearly arbitrary object geometries are achievable, no tooling is required, mating parts and fully assembled mechanisms can be fabricated in a single step, and multiple materials can be combined, allowing what has been referred to in the literature as ‘functionally graded’ material properties. It is to be noted, however, that the term ‘functionally graded’ as used in the art refers to the macroscopic combination of materials in a layer, akin to pieces of a jig-saw puzzle, but not to a localized, microscopic-scale heterogeneity or blending of materials. Notwithstanding, new features, parts, and even assembled components can be “grown” directly on already completed objects, suggesting the possibility of using SFF for the repair and physical adaptation of existing objects. On the other hand, a deposition process must be developed and tuned for each material, geometry is limited by the ability of the deposited material to support itself, by the (often poor) resolution and accuracy of the process, and multiple material and process interactions must be understood.
SFF has traditionally focused on printing passive mechanical parts or products in a single material, and research has emphasized developing new deposition processes, improving quality, resolution, and surface finish of fabricated objects, and broadening the range of single materials that can be employed by a given SFF process, including biocompatible polymers and other biomaterials and living cells. These improvements have allowed freeform fabrication to become a viable means of manufacturing finished functional parts, rather than only prototypes.
More recently, the greater utility of freeform fabricated objects having multiple materials has been recognized, prompting reexamination and novel research into processes which can fabricate objects using multiple materials and, which can thereby produce complex articles with a variety of functionality, including functionally graded materials. All of these systems still depend upon a small fixed set of deposition process technologies, and are therefore limited to the materials that can be adapted to those processes, by the effects of those particular processes on the materials, and by the fabrication rates and resolutions of those processes. For example, the system of U.S. Pat. No. 6,905,738 to Ringeisen et al. requires that for every material to be deposited, a two material system be developed comprising the material to be transferred, and a compatible matrix material that is vaporized by the laser in order to propel the transfer material to the substrate. In addition, this system has only demonstrated fabrication of thin films of materials; its ability to deposit many layers of materials is not well established. The system and method of Sun et al., “Multinozzle Biopolymer Deposition for Tissue Engineering Application,” 6.sup.th International Conference on Tissue Engineering, Orlando, Fla. (Oct. 10-13, 2003) and International Patent Application No. PCT/US2004/015316 to Sun et al., is limited to a fixed set of four deposition processes and requires that alginate materials be deposited into a bath of liquid cross linking agent, a limitation it shares with the work of Pfister et al., “Bio functional Rapid Prototyping for Tissue-engineering Applications: 3D Bioplotting Versus 3D Printing,” Journal of Polymer Science Part A: Polymer Chemistry 42:624-638 (2004) and Landers et al., “Desktop Manufacturing of Complex Objects, Prototypes and Biomedical Scaffolds by Means of Computer-assisted Design Combined with Computer-guided 3D Plotting of Polymers and Reactive Oligomers,” Macromolecular Materials and Engineering 282:17-21 (2000). In addition, none of these systems explicitly measures the properties of, and monitors and controls the conditions experienced by the fabrication materials, the fabrication substrate, and the article under construction before, during, and/or after fabrication as an intrinsic part of the fabrication process and manufacturing plan. The fabrication process is thus limited to the spatial control of material placement on relatively simple, passive substrates. Temporal control of the evolution of material properties is therefore not possible, and complex substrates whose state must be controlled and monitored continuously are not readily accommodated. Fabricating into or onto substrates, such as living organisms or devices which must remain in operation continuously, is problematic.
A major challenge in orthopedic tissue engineering is the generation of seeded implants with structures that mimic native tissue, both in terms of anatomic geometries and intra-tissue cell distributions. Previous studies have demonstrated that techniques such as injection molding (Chang et al., “Injection Molding of Chondrocyte/Alginate Constructs in the Shape of Facial Implants,” J. Biomed. Mat. Res. 55:503-511 (2001)) and casting (Hung et al., “Anatomically Shaped Osteochondral Constructs for Articular Cartilage Repair,” J. Biomech. 36:1853-1864 (2003)) of hydrogels can generate cartilage tissue in complex geometries. Other studies have investigated methods to reproduce regional variations in articular cartilage constructs by depositing multiple layers of chondrocytes (Klein et al., “Tissue Engineering of Stratified Articular Cartilage from Chondrocyte Subpopulations,” Osteoarthritis Cartilage 11:595-602 (2003)) or chondrocyte-seeded gels (Kim et al., “Experimental Model for Cartilage Tissue Engineering to Regenerate the Zonal Organization of Articular Cartilage,” Osteoarthritis Cartilage 11:653-664 (2003)). However, there remains no viable strategy for rapidly producing implants with correct anatomic geometries and cell distributions. Recently, advances in SFF techniques have enabled the deposition of multilayered structures composed of multiple chemically active materials (Malone et al., “Freeform Fabrication of 3D Zinc-Air Batteries and Functional Electro-Mechanical Assemblies,” Rapid Prototyping Journal 10:58-69 (2004)).
Tissue failure is a serious condition that can lead to deterioration of lifestyle and potentially to death. Medical advances in the past several decades have enabled the replacement of damaged tissues with mechanical or biochemical implants designed to mimic the function of the defective tissues. While these implants, such as, e.g., heart valves and hip-bone replacements, have demonstrated promising performance, such implants are susceptible to wear and degradation over time. More critically, these implants are incapable of repair or regeneration. This can become fatally problematic for infants and younger patients since their bodies can outgrow the implants and subsequently cause implant failure. Multiple surgeries would be necessary for implant resizing, but such operations can be traumatic for patients. While some conditions can be treated with implants, other failures in larger tissues, such as the heart and liver, are more serious since implants that can replace these tissues do not exist. As a result, patients rely on donors for treatment, but the demand of such organs far exceeds the available supply.
Tissue engineering has the potential to alleviate these limitations by providing living tissue replacements capable of growth and integration. A major technical challenge facing the field as a whole, however, is to both effectively fabricate tissue geometry and to specify (and/or control) locally heterogeneous tissue biomechanics. Creating complex, non-symmetric geometries that are applicable to tissue engineering can be approached using solid-freeform fabrication (SFF), or three-dimensional (3D) printing. Geometrically complex hard tissues including knee meniscus, bone, and cartilage can be fabricated. 3-D printing of highly extensible soft tissues, meanwhile, can be more challenging because gravity forces cause deposited viscous fluids to spread unless they are crosslinked, which limits the building of tall or non-self supportive geometries such as heart valves.
Pertinent object fabrication systems and methods are disclosed in U.S. Pat. Nos. 7,625,198, 7,939,003, and Pub. No. US 2011/0169193, the subject matters of which are hereby incorporated by reference in their entireties. To date, however, materials are deposited as separate, homogeneous materials, not as an interspersed or blended heterogeneous composite as would be required, for example, for truly functionally graded tissue engineering and fabrication. (i.e., composites with gradual variation in composition and structure, creating differences in material properties over the volume as, for example, by specifying distribution gradients as functions of spatial position).
The inventors have thus recognized the benefits and advantages provided by solutions to the aforementioned problems and known challenges in this field. These solutions include, among other things, the ability to simultaneously solid freeform fabricate and crosslink anatomically precise constructs in the form of stable, soft tissue structures; the ability to specify and fabricate tissues exhibiting localized heterogeneous (blended) biomechanics; the ability to access the print accuracy of the constructs.